It has been previously established (U.S. Patent App. Pub. No. 20050066381) that Protein Kinase C alpha (“PKC-α”) activity is increased in the pathological state of heart failure. Phosphatase Inhibitor Protein-1 (I-1) is a key regulator of cardiac contractility. I-1 is known to regulate cardiac contractility by inhibiting the activity of Protein Phosphatase-1 (“PP-1”). I-1's ability to inhibit PP-1 is further known to be regulated by phosphorylation. When threonine 35 of I-1 is phosphorylated by Protein Kinase A (PKA), PP-1 activity is inhibited, cardiac contractility is enhanced (Pathak, A., et al. 2005 Circ. Res 15:756′-66). It was previously shown that serine 67 (S67) is a PKC alpha phosphorylation site, and that a S67 I-1 mutant (for example, S67A) that mimics a constitutively unphosphorylated state, shows reduced phosphorylation relative to the wild type I-1. However, in vitro testing conditions failed to reveal any inhibition of PP-1 activity.
Heart failure, also called congestive heart failure, is a disorder in which the contractility of the heart muscle decreases, and the heart loses its ability to pump blood efficiently. It is estimated to affect over 10 million Americans, alone. Heart failure is almost always a chronic, long-term condition, and consumes an inordinate amount of medical intervention and human resource dollars. In particular, the consequences of heart failure to the rest of the body organs can be devastating both in terms of the overall reduction in productive life of the patient, and the expense of treatment. The condition may affect the right side, the left side, or both sides of the heart. As the pumping action of the heart is compromised, blood begins backing up into other areas of the body. Many organs and organ systems begin to suffer cumulative damage from lack of oxygen and nutrients.
There may be many underlying causes, and heart failure becomes more common with advancing age. Problematically, some patients with heart failure have no obviously noticeable symptoms, permitting serious peripheral conditions to manifest without the benefit of early intervention to ward off or abate the rate of serious organ damage. Regular screening and early detection will enable a patient to elect life style and dietary changes that will slow progress of the disease. Methods for large-scale screening, and early and accurate detection, as well as capability to prognose the development of heart failure, before significant organ damage is incurred, are clearly needed. In addition, particularly with elderly patients, there is a need for additional long-lasting treatment options that do not depend entirely on compliance with drug product ingestion schedules.